L0301P67 - Molecular Basis of Cancer 1
Cancer and DNA Damage *cancer develops due to damage to DNA *can be: **inherited (germ line errors) ***every cell in the body carries one copy of the DNA with that genetic defect **acquired (somatic errors) ***increased risk as person gets older due to higher exposure to carcinogens ***for some somatic mutations, only the cancer cells carry the DNA mutation, not the normal cells ***mutations are not passed onto offspring Cancer Causes *genetic – inherited (makes up 10% cancers) *acquired DNA damage can be induced by the following environmental exposures: **radiation **viruses **bacteria **chemical carcinogenesis **age ***lifetime exposure to carcinogens ***less effective DNA repair mechanisms **diet **UV light **and many others Ionising Radiation Effects *p53 - protein that keeps cells at the G1 phase allowing time for DNA repair if damaged DNA Damage *DNA can become damaged in many ways *spontaneous mutations arise because of chemical changes in nucleotides *carcinogens are compounds or chemicals that produce cancer **includes UV light, tobacco smoke, meat preservatives, ionising radiation *many present in food as “natural” carcinogens in food may account for up to 80% of carcinogens that we are exposed to in our diet **high fat and low fibre diet predisposes to cancer *obesity and chronic inflammation predisposes to some forms of cancer Susceptibility to DNA Damage *rapidly dividing cells *malfunctioning of DNA repair enzymes **substantial mutations **loss of DNA repair enzymes **rapid division = less time for DNA repair mechanisms to occur *cancer cells tend to have a more rapid cell cycle and gradually accumulate genetic damage to form a malignant tumour Cancers Caused by Viruses *may account for 15% cases of cancer *includes nasopharynx, cervical, lymphomas, liver cancer *viral infections that cause cancer are often “latent” (present but not clinically apparent) How *RNA virus or retrovirus (e.g. HIV virus) can transform a cell by altering critical genes that regulate cell growth *virus gene can be inserted upstream of the gene or within the coding sequence of the gene leading to over expression of a protein, or expression of a more active protein (e.g. HIV virus causes lymphoma) *DNA tumour viruses activate the host cells DNA replication machinery (e.g. papilloma virus causes carcinoma of the cervix) Inherited Cancer Predisposition Syndrome *about 10% result from inheritance of a mutated gene that predisposes to cancer *familial aggregation: **occurs in nearly every type of cancer *is due to: **exposure to the same carcinogens **genetic predisposition **combination of both *person with a parent/sibling who develops cancer at a young age (<40years) has 2 times risk of developing the same cancer *inherited cancer susceptibility genes identified for many forms of cancer **including breast and colon cancer   Features Suggestive of Inherited Cancer *several close or first degree relatives with a common cancer or with related cancers i.e. breast and ovary *two members of the same family with the same rare cancer *early age of onset of cancer *bilateral cancers in paired organs *tumours in two different organs in one individual (when they are not metastatic) Cancer and Inherited Predisposition *as about 10% of all cancers appear to run in families this has important consequences: **routine screening and procedures (e.g. colonoscopies) for familial cancers **genetic counselling ***understand their genetic predisposition (not a death sentence) ***avoid risk factors *treatment and prognosis may change (may be more aggressive or different treatment) *identification of the molecular mechanisms of cancer formation - design of potential novel therapies inherited Cancer Susceptibility Genes *identification of genes is in early stages *potent single gene defects that are highly predictive of cancer account for less than 10% of cases *however, in many cases the genetic predisposition must include the appropriate environmental stimulus **risk factors and exposure to carcinogens *defined dose of carcinogen may have different effects on individuals depending on the genetic make up (e.g. UV light exposure with people of different skin colours)  Cancer Susceptibility Genes *familial susceptibility to cancer can occur as: **susceptibility for a single type of cancer e.g. colon cancer **several types of cancer as part of a familial cancer predisposing syndrome e.g. multiple endocrine neoplasias *in some instances genes implicated to play a role in familial cancer are also implicated in sporadic cancer e.g. colon (not breast) *can be many different familial gene defects that lead to the same type of cancer Penetrance *the percentage of individuals with a specific genetic defect who will get the disease and to what extent *some people with inherited genes may be non-penetrant, i.e. do not have the disease Anticipation *where cases occur at younger ages in succeeding generations Phenocopy *family members who do no carry the familial mutation but appear to as they express a similar phenotype *family pedigrees more difficult to analyse Cancer Summary *has both genetic and environmental influences for expression of the phenotype *in general, apart from rare syndromes: **does not arise from a mutation or error in only one gene but rather arises from a series of cumulative genetic errors which result in a growth advantage *by the time a patient presents with cancer if the DNA of the cancer is examined, there may be over 7 significant mutations in specific genes in the cancer cell DNA Example: Colon Cancer Cancer Examples Breast Cancer *highly common - 1/10 women develop it *highly variable penetrance **inherited breast cancer syndromes: 40-70%, i.e. not everyone with the gene will ultimately develop breast cancer *this is important for cancer screening and family counselling Genetic Predisposition *causes up to 10% of breast cancer *hereditary breast cancer genes: **BRCA1 17q (51% express by age of 50) **BRCA2 13q (28% express by age of 50) *many families affected by breast cancer show an excess of ovarian, colon, prostatic and other cancers attributable to the same inherited mutation *most women, due to an inherited mutation, get breast cancer before the age of 65 *life time risk for: **sporadic breast cancer is 11% **breast cancer with BRCA1 and BRCA2 is 83- 88% by age of 70 ovarian cancer with BRCA1 and BRCA2 is 16-60%  Indicative Features of Increased Likelihood of BRCA Mutation *multiple cases of early onset breast cancer in the family *ovarian cancer (with a family history of breast or ovarian cancer) *breast and ovarian cancer in the same woman *bilateral (in both breasts) breast cancer *Ashkenazi Jewish heritage *male breast cancer Familial Adenomatous Polyposis *inherited mutation in APC gene *has ~100% penetrance *causes cells in colon to grow abnormally forming 1000s of polyps by 10 years of age *at least one of the many polyps will become malignant leading to colon cancer before the age of 40 years *only treatment for children: removal of the colon and use of a colostomy bag to collect waste Testing Screening for Familial Cancers Syndromes *prevention or early detection is the ultimate goal in the management of any patient with a familial cancer syndrome *screening from a young age includes gene testing and looking for early evidence of the clinical phenotype e.g. colonic polyps or breast lumps *benefits of screening long term need to be weighed against cost both physical and emotional for the patient   Testing for Mutations *affected family members may not be alive to test - proceed only with thorough counselling of the limitations and benefits of genetic testing *should result in early identification of at risk individuals and therefore increased detection and survival advantage for the patient *unless there is a highly suggestive family history, cancer susceptibility testing is not considered appropriate for screening unaffected individuals (except specific ethnic groups where specific mutations are more common)   Problems Associated with Testing *only 50% of the family will have the mutation **can only inherit one allele (if two = fatal) *> 500 mutations reported with majority of mutations result in a truncated protein *mutations can occur in almost any position **thus no simple test to screen for the specific mutation *molecular screening to detect a mutation for the first time in an affected individual or family is very technically demanding- sequence gene or look for truncation mutants *only positive test is informative i.e. detection of known or likely deleterious mutation **negative test does not mean the person will not develop cancer *cancer is a common disease therefore there is the high chance of phenocopies    